ES2698902T3 - Apparatus for application of a neuronal stimulus - Google Patents

Abstract

A device (100) for applying a neuronal stimulus and said device (100) comprises: at least two electrodes (122) configured to be located along a neuronal pathway with a population of fibers and a control unit (110) configured to : apply a sequence of therapeutic neuronal stimuli, which comprises a first stimulus and a second stimulus that are administered in a refractory period of the fiber population after the first stimulus, where the sequence of neuronal stimuli is applied sequentially to more than one of the at least two electrodes (122), where the stimulus parameters of the second stimulus differ from the stimulus parameters of the first stimulus so that the second stimulus is able to recruit an additional part of the fiber population from the first stimulus , and control the timing of the respective stimuli in the sequence to cause a spatio-temporal alignment of the responses evoked respective that propagate in a first direction along the nerve fiber to thereby cause correlation and sum of responses evoked in the first direction and cause a spatio-temporal misalignment of the respective evoked responses that propagate in a second direction opposite to the first direction along the nerve fiber, so as to relate the evoked responses that propagate in the second direction.

Description

DESCRIPTION

Apparatus for application of a neuronal stimulus

Description

Technical field

The present invention refers to the application of a neuronal stimulus and, in particular, refers to the application of a neuronal stimulus in a controlled manner by the use of electrodes implanted near the neuronal pathway.

BACKGROUND OF THE INVENTION

There is a variety of situations in which it is desirable to apply neuronal stimuli to generate a compound action potential (CAP). For example, neuromodulation is used to treat a variety of disorders including chronic pain, Parkinson's disease and migraine. A neuromodulation system applies an electrical impulse to the tissue to generate a therapeutic effect. When used to relieve chronic pain, the electrical impulse is applied to the spinal column (DC) of the spinal cord. Said system usually comprises an implanted electrical pulse generator and an energy source such as a battery that can be recharged by transcutaneous inductive transfer. An array of electrodes is connected to the pulse generator and located in the dorsal epidural space on the dorsal column. An electrical impulse applied to the dorsal column by an electrode causes the depolarization of neurons and the generation of propagated action potentials. The fibers that are stimulated in this way inhibit the transmission of pain from this segment in the spinal cord to the brain. To maintain the effects of pain relief, stimuli are applied substantially continuously, for example, at 100 Hz.

Although the clinical effect of spinal cord stimulation (SCS) has been established, the precise mechanisms involved are not fully understood. The DC is the target of the electrical stimulus, since it contains the Af afferent fibers of interest. Ap fibers mediate skin contact, vibration and pressure sensations, and are mechanoreceptors with a thick layer of myelin that respond to noxious stimuli. The dominant view is that the SCS stimulates only a small amount of Ap fibers in the DC. It is believed that the pain relief mechanisms of the SCS include antidromic activity evoked by Ap fibers with an inhibitory effect, and the orthodromic activity evoked by Ap fibers play a role in the suppression of pain. It is also believed that the SCS recruits Ap nerve fibers mainly in DC with antidromic spread of the evoked DC response in the dorsal horn through synapses of wide dynamic range neurons in an inhibitory manner.

In addition, it is possible to employ neuromodulation to stimulate efferent fibers, for example, to induce motor functions. In general, the electrical stimulus generated in a neuromodulation system triggers a neuronal action potential that has an inhibition or arousal effect. The inhibiting effects can be used to modulate an unwanted process, such as the transmission of pain, or to cause a desired effect, such as the contraction of a muscle.

The action potentials generated between a large number of fibers are summed to form a compound action potential (CAP). The CAP is the sum of responses of a large number of individual fiber action potentials. The registered CAP is the result of the depolarization of a large number of different fibers. The diameter of the fiber determines to a large extent the velocity of propagation and in the case of large myelinated fibers, such as are found in the entrance area of the dorsal root (DREZ), and close to the spine, the velocity can be greater than 60 ms-1. The CAP generated by the activation of a group of similar fibers is measured as a positive peak potential P1, then a negative peak N1, followed by a second positive peak P2. The passage of the recording electrode through the activation region as the action potentials propagate along the individual fibers causes this. Usually, an observed CAP signal will have a maximum amplitude in the microvolt range, while a stimulus applied to evoke the CAP is usually several volts.

For an efficient and convenient operation, it is necessary to maintain the amplitude of stimulus or load applied above a recruitment threshold, below which a stimulus would not recruit any neuronal response. It is also necessary to apply stimuli that are below a comfort threshold, above which perceptions of pain or discomfort are generated due to the increased recruitment of A5 fibers, which are sensitive nerve fibers with a thin layer of associated myelin. with sharp pain, feeling of pressure and cold. In virtually all neuromodulation applications, a single fiber response class is desired, but the stimulus waveforms employed can recruit other kinds of fibers that cause unwanted side effects, such as muscle contraction if motor fibers are recruited. The migration of electrodes and / or changes in posture of the implant recipient, any of which can significantly alter the recruitment generated by a given stimulus according to whether the stimulus is applied before or after the change of electrode position or the position of the user, make the task of maintaining adequate neuronal recruitment more difficult. Changes in posture alone can cause an effective and comfortable stimulus regimen to become painful or no longer effective.

EP 2243510 describes a device for selective high-frequency spinal cord modulation for inhibition with reduced side effects (paresthesia). By using a frequency greater than the refractory period of the target neurons, an asynchronous response is evoked.

MAHNAN, A ET ÁL .: "Measurement of the current-distance relationship using a novel refractory interaction technique", J. NEURAL ENG., Volume 6, No. 3, May 20, 2009 (2009-05-20), P. 036005, describes the sequential stimulation of two spatially separated electrodes and observes the response in order to determine the relationship between the threshold current and the electrode to fiber distance.

In the present description, it will be understood that the term "to understand", or variations such as "comprises" or "comprising", implies the inclusion of a mentioned element, integer or stage, or a group of elements, integers or stages, but not the exclusion of any other element, integer or stage, or group of elements, integers or stages.

Compendium of the invention

The present invention provides a device for applying a neuronal stimulus according to claim 1. Preferred embodiments are defined in the dependent claims. The aspects, embodiments and examples described herein, but not encompassed by the scope of claim 1, do not form part of the invention. This applies, in particular, to the methods described herein.

By providing a second stimulus to be delivered in the neuronal refractory period after the first stimulus, the present invention provides decorrelated or less correlated fiber responses that will evoke such stimuli.

The sequence of neuronal stimuli may comprise more than two stimuli, each administered in the refractory period after a previous stimulus in the sequence.

The sequence of neuronal stimuli can comprise stimuli of ascending amplitude.

More than one electrode sequentially applies the sequence of neuronal stimuli. In said embodiments, the second stimulus is preferably administered at a time subsequent to the first stimulus, which allows the cessation of the first stimulus and allows the propagation of a first neuronal response evoked by the first stimulus of the first electrode to the second electrode, so that the second stimulus is administered during a refractory period of neurons close to the second electrode after the activation of said neurons by the neuronal response evoked by the first stimulus. Additionally or alternatively, in some embodiments, consecutive electrodes located along an array of electrodes may apply the sequence of neuronal stimuli. The timing of the respective stimuli in the sequence is controlled to cause a spatiotemporal alignment of the respective evoked responses that propagate in a first direction along the nerve fiber to, in this way, cause correlation and sum of responses evoked in the first direction and causing a spatiotemporal misalignment of the respective evoked responses propagating in a second direction opposite the first direction along the nerve fiber, so as to de-correlate the evoked responses propagating in the second direction. It is beneficial to de-relate evoked potentials that propagate to the brain, where it is desired to avoid or minimize any perception of stimuli.

In some embodiments of the invention, the sequence of neuronal stimuli can be followed by a single stimulus that is not applied during the refractory period of any previous stimulus and that is not followed by any subsequent stimulus in the refractory period of the single stimulus. Said embodiments can be applied to make it possible to take a response measurement evoked after the single stimulus, to make possible the continuous adjustment of the stimulus parameters of the sequence of neuronal stimuli.

BRIEF DESCRIPTION OF THE DRAWINGS

Next, an example of the invention will be described with reference to the accompanying drawings, in which:

Figure 1 illustrates an implantable device suitable for implementing the present invention;

Figure 2a shows the response amplitude growth functions of Ap for spinal cord stimulation of sheep at 40, 80 and 120 ps, while Figure 2b shows the composite action potential recorded at equivalent loads for all three different impulse widths;

Figure 3 illustrates the sum of a sequence of superimposed neuronal responses;

Figure 4 is a schematic illustration of a sequence of potential pulses and the amplitude growth curve associated with the sequence;

Figure 5 illustrates the ERT responses to stimulus bursts with different frequencies;

Figure 6 illustrates a scheme of stimuli to generate stimuli that produce the synchronization of Ap activation in the antidromic direction and a desynchronizing activity in the orthodromic direction;

Figure 7 illustrates experimental results obtained by applying a series of four ascending amplitude stimuli on four electrodes adjacent to a sheep spinal cord;

Figure 8 illustrates experimental results obtained in response to bursts of stimuli of intervals between different stimuli and

Figure 9 illustrates a suitable response controller for controlling the parameters of the stimulus burst in an automated manner.

Description of the preferred embodiments

Figure 1 illustrates an implantable device 100 suitable for implementing the present invention. The device 100 comprises an implanted control unit 110 that controls the application of a sequence of neuronal stimuli according to the present invention. In this embodiment, the unit 110 is also configured to control a measurement process to obtain a measurement of a neuronal response evoked by a single stimulus administered by one or more of the electrodes 122. The device 100 also comprises an array of electrodes 120 which it consists of an arrangement of three by eight electrodes 122, each of which can be used selectively either as a stimulating electrode or sensing electrode, or both.

The activation and simultaneous suppression of different areas of tissue for the treatment of a variety of neurological disorders is highly desirable. For the treatment of incontinence, the activation or reduction of urination without contraction of the sphincter is very desirable. The objective of the spinal cord stimulation is to block the transmission of pain signals from fibers A6 and C by the inhibition effect of Ap fiber activation. The ascending Ap fibers produce a psychophysiological response that results in paresthesia (described as tingling). by the receivers). A variety of ways to reduce or eliminate this effect have been suggested. It has been reported that burst mode stimulation or continuous stimulation at high frequencies can produce pain relief without added paresthesia, although the mechanisms are not clearly understood.

One possible explanation is that the high frequency stimulus produces a very uncorrelated neuronal activation pattern in ascending Ap tracts. The high frequency stimulus generates the continuous activation of the fibers and produces a randomized activation pattern. The recovery time (refractory period) between each fiber is slightly different and if a depolarization potential is present as the fiber leaves the refractory period, it will depolarize again, but not synchronized with other fibers that can still be found in its refractory periods. The net result is a randomization of the activation pattern and a return of the stochastic response in the fiber.

The measurements of the evoked neuronal response provide a direct measure of the degree of correlation of the activation pattern. Figure 2a shows the amplitude functions of response amplitude Ap with respect to the amplitude of the stimulus for stimulation of the spinal cord of sheep at 40, 80 and 120 ps. Recruitment is related to the load and, therefore, the stimulus at 1 mA for 120 ps produces a load equivalent to stimulus at 3 mA for 40 ps, and the vertical lines highlight two respective points of administration of the same load for each swept. Figure 2b shows the composite action potential recorded in equivalent loads for the three different pulse widths. The peak height is smaller and the response peak evoked is wider with the equivalent load for the longer pulse width than for the shorter pulse width and this is indicative of a less correlated evoked response.

The probability that any individual fiber responds is a function of the properties and history of the fiber and the amplitude of the current pulse. Although short and long pulses for an equivalent load can recruit the same amount of fibers, the longer smaller current amplitude pulse will recruit the fibers for a longer time than the shorter high current pulse width.

Patients report preference for stimuli with longer pulse widths and the reason for this preference may be that the perceptual side effect is lower because there is less correlation between fiber activation. Given this observation, very poorly corrected responses can generate much smaller psychophysical side effects, such as tingling sensations and paresthesia. The evoked responses measured for the longer pulse widths are broader in Figure 2b, indicating less correlation in the activation pattern.

The measurement of the evoked response provides a unique way to evaluate the degree of correlation between fibers in a group because the width of the peak and the amplitude of the measured response are directly related to the degree of temporal synchronization of the action potentials of individual fibers whose sum forms the compound action potential. The objective of the stimulus design is to achieve a high level of recruitment at the segmental level and a low level of correlation for the ascending segments. The measurement of neuronal response obtained in each detection electrode can be taken according to the techniques described in Daly (US 2007/0225767). Additionally or alternatively, the measurement of neuronal response can be carried out according to the techniques described in Nygard (US Patent No. 5,758,651). Additionally or alternatively, the neural response measure can be carried out according to the techniques described in Australian Provisional Patent Application No. 2011901817 filed concurrently with the present on behalf of National ICT Australia Ltd under the title "Method and apparatus for measurement of neural response " and subsequently published as WO 2012/155183.

It is possible to measure the degree of correlation in a response evoked with such techniques and it is possible to design pulse sequences to produce evoked responses of a desired character. A typical recruitment curve is shown in Figure 2a. The strength of the Ap potentials is directly related to the amount of fibers recruited and, consequently, the stimulus to successively increasing successive amplitudes will recruit successively more fibers. If the impulse time is marked to occur within the refractory period of the excited neurons from the previous impulse, then it is possible to select subpopulations of different neurons with each impulse.

The moment of each impulse can be arranged in such a way that the CAPs in transit of each individual impulse cancel each other when they are added at a certain distance from the stimulus site. This indicates the degree of desynchronization between the fibers and how the detection input is based on the correlation of activation patterns, sensation is reduced (paresthesia). However, the activation of the inhibition effect of the Ap fibers at the segmental level is not reduced, which allows the inhibition with Ap of the propagation of A5 and C to occur, as desired.

Figure 3 illustrates the principle of applying a sequence of neuronal stimuli and allowing the respective evoked responses 302, 304, 306 to propagate along the fiber. In 308 the numerical sum of five of said superposed composite action potentials is shown, of which only three appear in Figure 3. Figure 3 shows the effect of the sum of the five-pulse evoked response with the time intervals between pulses arranged as a consequence of the arrival of the response waveform evoked at a designated point along the array of electrodes, such that the average signal recorded at that point is minimized. The time difference between each cathodic pulse for the data illustrated in Figure 3 is 0.3 ms. Figure 4 is a schematic illustration of a sequence of potential pulses (lower) and the amplitude growth curve associated with the (upper) sequence. Current levels A-C are represented in both parts of Figure 4. The initial amplitude pulse A can be expected to recruit only a part of the available population. Then, it can be expected that the application of the later amplitude stimulus will recruit an additional, but not all, of the available neuronal population, even though stimulus B is applied during the refractory period after stimulus A. Similarly, it can be expected that stimulus C will recruit an additional part of the available neuronal population. C can be applied during the refractory period only of stimulus B or, possibly, within the refractory period of both stimuli A and B. Therefore, it can be expected that the sequence of ABC neural stimuli may recruit a similar amount of population The available neuronal would be the one that would recruit the C stimulus if applied alone, however, the progressive recruitment of parts of the neuronal population at progressive moments implies a significantly derelated response evoked in comparison with the response resulting from a single stimulus of amplitude C.

It is possible to greatly extend the concept of selection of stimulus sequences based on the recorded ERT parameters. For example, the example in Figure 4 demonstrates the achievement of an uncorrelated group response in the fiber population that is stimulated.

Figure 5 illustrates the ERT responses to stimulus bursts with different frequencies. The degree of correlation can be inferred from the ERT signal. A normal stimulus can be used to evaluate the amplitude of stimulus response in the absence of any additional desynchronizing pulses. The amplitude of the individual probe pulse is adjusted to represent the total load that is administered over time for the corresponding desynchronizing pulse train. The amplitude of the measured response of the individual probe pulse represents a fully synchronized response. Then, the train of desynchronizing pulses is emitted and the response is measured. The ratio of the two responses is proportional to the level of synchronization and, therefore, can be used as a control parameter to adjust the characteristics of the device. For example, the patient can adjust the control parameter so that it is possible for the patient to adjust the level of paresthesia that is perceived. The detection system of a change of state in neuronal tissue can also use the control variable for diagnostic purposes.

The device can apply an individual non-de-correlating stimulus to the nerve periodically or occasionally to elicit an evoked response which, then, is used as the input to the control loop. Said probe stimulus can be adjusted so that its load is equivalent to the load presented by the desynchronizing stimuli. Then, the frequency of the probe pulse can be adjusted to minimize perceptual side effects. You can also adjust the probe frequency on demand, which, for example, responds more quickly to changes in movement.

The conduction of the compound action potentials occurs both orthodromically (ascending in the column) and antidromic (in the downward direction in the column). A careful selection of the stimulus design can be used to create a situation in which the degree of synchronization can be different in both directions and this can be controlled. For example, one may wish to generate stimuli that produce synchronization of the activation of Ap in the antidromic direction and a desynchronizing activity in the orthodromic direction. A possible scheme for doing this is illustrated in Figure 6. A stimulus pulse, preferably two-phase, is discharged at an electrode (electrode 0 indicated on the left side of Figure 6). In a subsequent time interval, a stimulus pulse 2 is discharged between two other electrodes. For purposes of convenience, this is illustrated in Figure 6 as the electrode (number 1) adjacent to the first electrode). The second discharge is arranged to occur at a time and place such that its resulting CAP propagation to an electrode (eg, "+6") in one direction (the upward direction in Figure 6) is summed with another evoked CAP . In contrast, in the other direction (the downward direction in Figure 6), the respective PACs do not align or correlate, e.g., when observed at the -3 electrode.

One possible way to achieve this directional selectivity of the CAP correlation, but not the only one, is to arrange a series of stimulus pulses with an interval between pulses equal to the propagation time difference necessary for the desynchronization of the CAP in the direction upward.

It should be noted that it is not necessary that the order in which the stimuli are presented be sequential. The amplitudes of the individual stimuli can also be varied according to the scheme of Figure 4. The moment of presentation can also oscillate to adjust the moment in time.

Figure 7 illustrates experimental results obtained by applying a series of four ascending amplitude stimuli on four electrodes adjacent to a sheep spinal cord. Each stimulus was a tripolar stimulus for which the respective central electrode was, in order, the electrode E7, E8, E9 and E10, which are the four electrodes located in the center of a linear electrode array of 16 electrodes. Each stimulus was biphasic, each phase had a pulse width of 20 ps and the interphase space was 10 ps. The stimuli had ascending amplitudes of 2 mA, 2.5 mA, 3 mA and 3.5 mA, respectively. The interval between stimuli between each successive pair of stimuli in the respective electrodes was 33 ps, so that the time between pulses was 83 ps, to optimally correlate the net evoked response in the antidromic direction (ie, caudal) . As can be seen in Figure 7, the antidromic response 704 measured at the electrode E16 of the four substituent parts was correlated and has a large amplitude. In contrast, the four orthodromic responses did not correlate and produced a net response 702 measured at the E3 electrode that had a very small amplitude compared to the 704 response that moves in the opposite direction, although both were produced by the same Burst of four stimuli.

Figure 8 shows the responses measured at intervals between different stimuli. As can be seen, the interval between stimuli greatly affects the effectiveness of this technique, so that the preferred embodiments provide a response loop to optimize this parameter and all other parameters of the stimulus when establishing the burst of stimuli. Figure 9 illustrates a suitable response controller for controlling the parameters of the stimulus burst in an automated manner, so that the evoked responses measured in each direction are used to determine the stimulus parameters required to achieve a desired directional effect. Said automated response allows the relatively large parameter space to be explored to identify bursts parameters of optimal stimuli.

Those skilled in the art will understand that multiple variations and / or modifications to the invention are possible as illustrated in the specific embodiments without departing from the scope of the invention as defined in the claims. Accordingly, the claims herein should be considered in all respects as illustrative and not as restrictive.

Claims (8)

1. A device (100) for applying a neuronal stimulus and said device (100) comprises: at least two electrodes (122) configured to be located along a neuronal path with a population of fibers and a control unit (110) configured to: applying a sequence of therapeutic neuronal stimuli, which comprises a first stimulus and a second stimulus that are administered in a refractory period of the fiber population subsequent to the first stimulus, wherein the sequence of neuronal stimuli is applied sequentially to more than one of the at least two electrodes (122), wherein the stimulus parameters of the second stimulus differ from the stimulus parameters of the first stimulus so that the second stimulus is able to recruit an additional part of the fiber population with respect to the first stimulus, and control the moment of the respective stimuli in the sequence to cause a space-time alignment of the respective evoked responses that propagate in a first direction along the nerve fiber to, in this way, cause correlation and sum of responses evoked in the first address and cause a spatiotemporal misalignment of the respective evoked responses that propagate in a second direction opposite the first direction along the nerve fiber, so as to de-correlate the evoked responses propagating in the second direction. The device of claim 1, wherein the sequence of neuronal stimuli comprises more than two stimuli, each of which is administered in a refractory period subsequent to a previous stimulus in the sequence. 3. The device of claim 1 or claim 2, wherein the sequence of neuronal stimuli comprises ascending amplitude stimuli. The device of claim 1, wherein the control unit (110) is configured to deliver the second stimulus at a time subsequent to the first stimulus, which allows the cessation of the first stimulus and allows the propagation of a first neuronal response evoked by the first stimulus of a first electrode (122) to a second electrode (122), so that the second electrode (122) administers the second stimulus during a refractory period of neurons close to the second electrode after the activation of said neurons by the neuronal response evoked by the first stimulus. The device of any of claims 1 to 4, wherein the control unit is configured to apply the sequence of neuronal stimuli by consecutive electrodes (122) located along an array of electrodes (120). The device of any of claims 1 to 5, wherein the first direction is caudal. The device of any of claims 1 to 6, wherein the control unit (110) is additionally configured to apply a single stimulus outside the refractory period of any previous stimulus and is not followed by any subsequent stimulus in the refractory period of the stimulus. unique stimulus, in order to make it possible to take a response measure evoked after the single stimulus. The device of claim 7, wherein the control unit is further configured to utilize the response measurement evoked for the response control of the stimulus parameters of the sequence of neuronal stimuli.